Paclitaxel of formula1, a terpene taxane derivative, is a potent anti-tumor chemotherapeutics having a broad spectrum of anti-leukemia and anti-tumor activity. Accordingly, many concerns have been focused on this compound in both area of biology and chemistry. Paclitaxel has also been allowed to be commercially marketed as an anti-tumor agent against ovarian cancer and breast cancer in several countries including the United States.
Hitherto, paclitaxel has been provided by separation from the bark of Taxus brevifolia which is a kind of western yew tree. However, since the separation and purification procedures are very burdensome and further only small amount of paclitaxel is contained in the bark of that evergreen tree, the amount of paclitaxel thus provided can hardly meet the more and more increasing commercial need.
Recently, the chemists have extensively studied about semi-syntheses which are applicable for preparing paclitaxel and about new synthetic methods for the same compound including processes for preparing the intermediates. However, a lot of synthetic methods reported heretofore have not shown a satisfactory result.
For example, WO 93/06094 discloses a process for preparing paclitaxel by reacting a beta-lactam compound and 7-triethylsilyl-baccatin III, then by deprotecting, as depicted in the following reaction scheme 1. Now, this is recognized as the shortest procedure to obtain the desired paclitaxel compound. ##STR3## in which TES represents triethylsilyl, and hereinafter has the same meaning.
Although this method has a merit that the coupling reaction can be readily carried out by using the beta-lactam compound, it also has many disadvantages such that the synthesis of the beta-lactam compound itself is very difficult, the coupling reaction should be proceeded at a low temperature of -45.degree. C. under an anhydrous condition, a toxic acid having a strong corrosive action against glass products as well as properties hard to treat (i.e.,48% HF) should be used during the process for removing the triethylsilyl (TES) group used as a protecting group for a taxane derivative, etc.
In addition, as depicted in the following reaction scheme 2, a process wherein an oxazolidine compound instead of the beta-lactam is coupled with a 7-Troc-baccatin III in the presence of dicyclohexylcarbodiimide or 2-dipyridylcarbonate is described in Commercon et al., Tetrahedron Letters, pp5185-5188, 1992. ##STR4## in which Boc represents t-butoxycarbonyl,
In the above process for preparing paclitaxel, a new protecting group for the taxane derivative (-Troc) which is different from that used in the prior process of reaction scheme 1 (-TES) has been used. However, according to the use of this novel protecting group, more reaction steps should be carried out to obtain the desired product, vigorous reaction conditions are required for the protection as well as deprotection reaction, and as a result the total yield becomes low. Therefore, the process of reaction scheme 2 is understood inferior to that of reaction scheme 1.
In the process of reaction scheme 2, an oxazolidine derivative is coupled with a taxane derivative to prepare paclitaxel. As the known oxazolidine derivatives which have been used for such a purpose, a compound represented by the following formula 6 (see, WO 94/10169) and a compound represented by the following formula 7 (see, Korean Patent Appln. No. 95-703548) can be mentioned. ##STR5## in which R.sub.a represents phenyl or R.sub.f O, wherein R.sub.f represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl or heterocyclic compound containing nitrogen atom,
The oxazolidine derivative of formula 6 above has various substituents at 2-position of the ring and the amine group at 3-position is necessarily protected by a substituted carbonyl group. It is because the amine group at 3-position is apt to react with the carboxylic acid at 5-position of another oxazolidine molecule if it is not protected. This kind of side reaction has greater reactivity than the coupling reaction between the oxazolidine derivative and the taxane derivative, and as a result the coupling reaction cannot be carried out favorably. Another case can be seen from the oxazolidine derivative of formula 7. That is, in case the substituent at 2-position of the oxazolidine ring is trihalomethyl or phenyl substituted by trihalomethyl, the desired coupling reaction can be carried out without any side reaction such as self coupling between oxazolidine molecules although the amine group at 3-position is not protected. If no protection for the amine group at 3-position of oxazolidine ring is required, several advantages including no need for removing the protecting group at a later step may be anticipated.
While, another process for preparing paclitaxel, as depicted in the following reaction scheme 3, is disclosed in Korean Patent Appln. No. 94-702930. ##STR7##
In the above process, paclitaxel is prepared by coupling an oxazoline derivative with a taxane derivative having a hydroxy group directly attached to C-13 to produce a taxane derivative having an oxazoline substituent, opening the oxazoline ring, then deprotecting. When such an oxazoline derivative substituted by a phenyl group at 2-position and a taxane derivative protected with triethylsilyl group are used as starting materials, however, opening reaction of the oxazoline ring and deprotection reaction may not readily performed. That is, severe reaction conditions such as strong acidity and long reaction time (i.e., IN-HCl (5.5 eq.), 0.degree. C., 21 hrs) are required, nevertheless, productivity and reaction yield are still low.
As aforementioned, the earlier developed processes for preparing paclitaxel use various side chain substituents such as beta-lactam derivative, oxazolidine derivative, or oxazoline derivative. But, all those substituents have some problems, for example, synthesis of itself or coupling with a taxane derivative is difficult, opening the substituent ring requires severe conditions, etc.
Another important point that should be considered is the choice of the protecting group for taxane derivative. As the protecting groups for taxane derivative reported up to the present, triethylsilyl and trichloro-ethoxycarbonyl can be mentioned. In order to remove such protecting groups, extremely acidic conditions or extended reaction time such as reacting for 14 hours in the presence of 48HF/pyridine; reacting for 4 hours in formic acid solvent; reacting at a condition of zinc, AcOH/MeOH=1/1 and 60.degree. C.; reacting for 30 hours in 0.5% HCl/EtOH; etc. are usually required. Moreover, those protecting groups have the following problems. In the case of triethylsilyl group, an excessive amount (20 eq.) of the expensive triethylsilyl chloride should be used in the protection reaction (see, WO 93/06094); and in the case of trichloroethoxycarbonyl group, complicated synthetic pathway should be applied for preparing the protected taxane derivative since this protecting group has no selectivity (see, Commercon, et al., Tetrahedron Letters, pp5185-5188, 1992).